Juvenile idiopathic arthrifis (JIA) is the most common rheumatic disease of childhood and constitutes a heterogeneous group of pediatric arthropathies that range from mild and self-limited to severe and disabling. The etiology of JIA is complex and includes genetic factors. Our recent genome-wide association study (GWAS) in JIA identified single nucleotide polymorphisms (SNPs) as risk factors for development of disease. These included SNPs in genes that are associated with other autoimmune diseases, as well as SNPs in genes uniquely associated with JIA. Two genes strongly implicated as risk factors have plausible functions in disease that are supported by our gene expression data. Specifically, JMJD1C is a histone demethylase that may be involved in transcripfional programming and determining cell fate, and PTPN2 is a key regulator of immune cell signaling including regulation of JAK-STAT pathways. In the first cycle of the Program Project, analysis of peripheral blood mononuclear cell (PBMC) samples in patients prior to the start of methotrexate (MTX), demonstrated that transcripts for both PTPN2 and JMJD1C were expressed in greater amounts in patients who subsequentiy did not respond to MTX compared to those who did respond Furthermore, increased expression of both genes was associated with a PBMC T Cell Signature that was associated with persistently active disease and will be studied in Project 1. In fact, JMJD1C was one of the 50 genes that defined this T Cell Signature. Based on these findings, we hypothesize that genetic variability in PTPN2 and/or JMJD1C is important to both JIA susceptibility and clinical variability in treatment response Following from this, an overiap is predicted between the biological pathways influenced by effective drugs and pathways that influence disease risk. The gene expression datasets available in this Program Project place us in a particularly powerful position to evaluate relationships between genetic variants and gene expression signatures. We will focus on PTPN2 and JMJD1C as two key players, potentially risk factors for disease (or sub-phenotype) and predictors of outcomes. We propose to first catalogue genefic variation in both the JMJD1C and PTPN2 regions using re-sequencing and fine mapping approaches. Next, we will utilize the gene expression datasets being developed within the Program Project to complete an integrative analysis of genotype and gene expression data. Finally, we will evaluate risk-altering variants relative to differential splicing, histone methylation (JMJD1C), and STAT1 phosphorylation {PTPN2). Our long-term objective is to understand the molecular basis for JIA in a way that reduces heterogeneity and informs the development of DNA tests that guide treatment choices in JIA. RELEVANCE (See instructions):